Tratamiento moderno de la hemofilia y el desarrollo de terapias innovadoras.

Modern treatment of hemophilia and development of innovatives therapies.

  • Arlette Ruiz-Sáez Banco Municipal de Sangre, Caracas, Venezuela
Palabras clave: hemofilia, tratamiento, innovaciones, terapia génica

Resumen

La hemofilia es una enfermedad hemorrágica resultante de mu-taciones en el gen del factor VIII (F8) de la coagulación en el caso de la hemo-filia A o en el gen del factor IX (F9) en el caso de la hemofilia B, siendo ambas formas indistinguibles clínicamente. El fenotipo clínico usualmente refleja la actividad del factor en plasma y la principal complicación del tratamiento es el desarrollo de aloanticuerpos neutralizantes. El tratamiento moderno de la hemofilia comienza a despuntarse en la década de 1970 con la disponibilidad de concentrados de factores de la coagulación de origen plasmático, el inicio de programas de profilaxis y el manejo multidisciplinario de la condición. Pos-teriormente, la producción de concentrados seguros, debidamente inactivados o de origen recombinante, facilitó la individualización de la terapia y el desa-rrollo de los agentes baipás mejoró el tratamiento de pacientes con inhibidores. Para todas esas opciones, la gran limitante ha sido la necesidad de frecuentes infusiones endovenosas por un tiempo indefinido. La biotecnología ha permi-tido el desarrollo de concentrados de factor VIII y IX de vida media plasmática extendida y a la producción de terapias novedosas, diferentes a la terapia de remplazo, que mejoran la coagulación o inhiben las vías anticoagulantes natu-rales. Por último, los progresos en la terapia génica como potencial cura de la condición generan grandes expectativas. Si bien estos avances ofrecen alterna-tivas terapéuticas para pacientes con o sin inhibidores, aún están por definirse aspectos relacionados a sus indicaciones, monitorización y seguridad a corto y largo plazo.

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Gruppo RA, Malan D, Kapocsi J, Nemes L, Hay CRM, Boggio L, Chowdary P, Tagariello G, von Drygalski A, Hua F, Scaramozza M, Arkin S. Marzeptacog alfa (activated) Study Group Investigators. Phase 1, single- dose escalating study of marzeptacog alfa (activated), a recombinant factor VIIa variant, in patients with severe hemophilia. J Thromb Haemost 2018;16(10):1984-1993.

Biron-Andreani C, Schved JF. Eptacog beta: a novel recombinant human factor VIIa for the treatment of hemophilia A and B with inhibitors. Expert Rev Hematol 2019;12(1):21-28.

Ljung R, Auerswald G, Benson G, Dolan G, Duffy A, Hermans C, Jiménez-Yuste V, Lambert T, Morfini M, Zupančić-Šalek S, Santagostino E. Inhibitors in haemophilia A and B: Management of bleeds, inhibitor eradication and strategies for difficult- to-treat patients. Eur J Haematol 2019; 102(2), 111–122.

Hay CR, DiMichele DM. International Immune Tolerance Study. The principal results of the International Immune Tolerance Study: a randomized dose comparison. Blood 2012;119(6):1335-1344.

Collins P, Chalmers E, Alamelu J, Hay C, Liesner R, Makris M, Mathias M, Payne J, Rangarajan S, Richards M, Talks K, Tunstall O, Williams M, Hart DP. First-line im- mune tolerance induction for children with severe haemophilia A: A protocol from the UK Haemophilia Centre Doctors’ Organisation Inhibitor and Paediatric Working Parties. Haemophilia 2017;23(5):654-659.

Carcao M, Escuriola-Ettingshausen C, Santagostino E, Oldenburg J, Liesner R, Nolan B, Bátorová A, Haya S, Young G; Future of Immunotolerance Treatment Group. The changing face of immune to- lerance induction in haemophilia A with the advent of emicizumab. Haemophilia 2019;25(4):676-684.

Pipe SW. Delivering on the promise of gene therapy for haemophilia. Haemophilia 2020 Jun 3. doi: 10.1111/hae.14027. Epub ahead of print. Pasi KJ, Rangarajan S, Mitchell N, Lester W, Symington E, Madan B, Laffan M, Russell CB, Li M, Pierce GF, Wong WY. Multiyear Follow-up of AAV5-hFVIII-SQ Gene Therapy for Hemophilia A. N Engl J Med 2020;382(1):29-40.

Nathwani AC, Reiss UM, Tuddenham EG, Rosales C, Chowdary P, McIntosh J, Della Peruta M, Lheriteau E, Patel N, Raj D, Riddell A, Pie J, Rangarajan S, Bevan D, Recht M, Shen YM, Halka KG, Basner-Ts- chakarjan E, Mingozzi F, High KA, Allay J, Kay MA, Ng CY, Zhou J, Cancio M, Morton CL, Gray JT, Srivastava D, Nienhuis AW, Davidoff AM. Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N Engl J Med 2014;371(21):1994- 2004.

George LA, Sullivan SK, Giermasz A, Rasko JEJ, Samelson-Jones BJ, Ducore J, Cuker A, Sullivan LM, Majumdar S, Teitel J, McGuinn CE, Ragni MV, Luk AY, Hui D, Wright JF, Chen Y, Liu Y, Wachtel K, Winters A, Tiefenbacher S, Arruda VR, van der Loo JCM, Zelenaia O, Takefman D, Carr ME, Couto LB, Anguela XM, High KA. Hemophilia B gene therapy with a high- specific-avtivity Factor IX variant. N Engl J Med 2017;377(23):2215-2227.

Von Drygalski A, Giermasz A, Castaman G, Key NS, Lattimore S, Leebeek FWG, Miesbach W, Recht M, Long A, Gut R, Sawyer EK, Pipe SW. Etranacogene deza- parvovec (AMT-061 phase 2b): normal/near normal FIX activity and bleed cessation in hemophilia B. Blood Adv 2019;3(21):3241- 3247.

Peyvandi F, Garagiola I. Clinical advances in gene therapy updates on clinical trials of gene therapy in haemophilia. Haemophilia 2019;25(5):738-746.

Pierce GF, Kaczmarek R, Noone D, O’Mahony B, Page D, Skinner MW. Gene therapy to cure haemophilia: Is robust scientific inquiry the missing factor? Haemophilia 2020 Sep 10. doi: 10.1111/ hae.14131. Epub ahead of print. http://fdaaa.trialstracker.net/trial/ NCT03370913/

Stonebraker JS, Bolton-Maggs PHB, Brooker M, Evatt B, Iorio A, Makris M, O’Mahony B, Skinner MW, Coffin D, Pierce GF, Tootoonchian E. The World Federation of Hemophilia Annual Global Survey 1999- 2018. Haemophilia 2020;26(4):591-600.

Pipe SW, Shima M, Lehle M, Shapiro A, Chebon S, Fukutake K, Key NS, Portron A, Schmitt C, Podolak-Dawidziak M, Selak Bienz N, Hermans C, Campinha-Bacote A, Kiialainen A, Peerlinck K, Levy GG, Jiménez-Yuste V. Efficacy, safety, and pharmaco- kinetics of emicizumab prophylaxis given every 4 weeks in people with haemophilia A (HAVEN 4): a multicentre, open-label, non- randomised phase 3 study. Lancet Haematol 2019;6(6):e295-e305.

Shima M, Nogami K, Nagami S, Yoshida S, Yoneyama K, Ishiguro A, Suzuki T, Taki M. A multicentre, open-label study of emicizumab given every 2 or 4 weeks in children with severe haemophilia A without inhibitors. Haemophilia 2019;25(6):979-987. doi: 10.1111/hae.13848. Epub 2019 Sep 12.

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Samuelson Bannow B, Recht M, Négrier C, Hermans C, Berntorp E, Eichler H, Mancuso ME, Klamroth R, O’Hara J, Santagostino E, Matsushita T, Kessler C. Factor VIII: Long-established role in haemophilia A and emerging evidence beyond haemostasis. Blood Rev 2019;35:43-50.

Shima M. Bispecific antibodies and advances in non-gene therapy options in Hemophilia. Res Pract Thromb Haemost 2020;4(4):446-454.

Harkins Druzgal C, Kizilocak H, Brown J, Sennett M, Young G. Neutralizing antidrug antibody to emicizumab in a patient with severe hemophilia A with inhibitors: New case with detailed laboratory evaluation [published online ahead of print, 2020 Jun 16]. J Thromb Haemost. 2020;10.1111/ jth.14957. doi:10.1111/jth.14957

Makris M, Iorio A, Lenting PJ. Emicizumab and thrombosis: The story so far. J Thromb Haemost 2019;17(8):1269-1272.

Pasi KJ, Rangarajan S, Georgiev P, Mant T, Creagh MD, Lissitchkov T, Bevan D, Austin S, Hay CR, Hegemann I, Kazmi R, Chowdary P, Gercheva-Kyuchukova L, Mamonov V, Timofeeva M, Soh CH, Garg P, Vaishnaw A, Akinc A, Sørensen B, Ragni MV. Targeting of antithrombin in Hemophilia A or B with RNAi therapy. N Engl J Med 2017;377(9):819-828.

Eichler H, Angchaisuksiri P, Kavakli K, Knoebl P, Windyga J, Jiménez-Yuste V, Hyseni A, Friedrich U, Chowdary P. A randomized trial of safety, pharmacokinetics and pharmacodynamics of concizumab in people with hemophilia A. J Thromb Haemost. 2018;16(11):2184-2195.

Shapiro AD, Angchaisuksiri P, Astermark J, Benson G, Castaman G, Chowdary P, Eichler H, Jiménez-Yuste V, Kavakli K, Matsushita T, Poulsen LH, Wheeler AP, Young G, Zupancic-Salek S, Oldenburg J. Subcutaneous concizumab prophylaxis in hemophilia A and hemophilia A/B with inhibitors: phase 2 trial results. Blood 2019;134(22):1973-1982.

Patel-Hett S, Martin EJ, Mohammed BM, Rakhe S, Sun P, Barrett JC, Nolte ME, Kuhn J, Pittman DD, Murphy JE, Brophy DF. Marstacimab, a tissue factor pathway inhibitor neutralizing antibody, improves coagulation parameters of ex vivo dosed haemophilic blood and plasmas. Haemophilia 2019;25(5):797-806.

Meeks SL & Leissinger CA. The evolution of factor VIIa in the treatment of bleeding in haemophilia with inhibitors. Haemophilia 2019; 25(6), 911–918.

Gruppo RA, Malan D, Kapocsi J, Nemes L, Hay CRM, Boggio L, Chowdary P, Tagarie- llo G, von Drygalski A, Hua F, Scaramozza M, Arkin S. Marzeptacog alfa (activated) Study Group Investigators. Phase 1, single- dose escalating study of marzeptacog alfa (activated), a recombinant factor VIIa variant, in patients with severe hemophilia. J Thromb Haemost 2018;16(10):1984-1993.

Biron-Andreani C, Schved JF. Eptacog beta: a novel recombinant human factor VIIa for the treatment of hemophilia A and B with inhibitors. Expert Rev Hematol 2019;12(1):21-28.

Ljung R, Auerswald G, Benson G, Dolan G, Duffy A, Hermans C, Jiménez-Yuste V, Lambert T, Morfini M, Zupančić-Šalek S, Santagostino E. Inhibitors in haemophilia A and B: Management of bleeds, inhibitor eradication and strategies for difficult- to-treat patients. Eur J Haematol 2019; 102(2), 111–122.

Hay CR, DiMichele DM. International Immune Tolerance Study. The principal results of the International Immune Tolerance Study: a randomized dose comparison. Blood 2012;119(6):1335-1344.

Collins P, Chalmers E, Alamelu J, Hay C, Liesner R, Makris M, Mathias M, Payne J, Rangarajan S, Richards M, Talks K, Tunstall O, Williams M, Hart DP. First-line immune tolerance induction for children with severe haemophilia A: A protocol from the UK Haemophilia Centre Doctors’ Organisation Inhibitor and Paediatric Working Parties. Haemophilia 2017;23(5):654-659.

Carcao M, Escuriola-Ettingshausen C, Santagostino E, Oldenburg J, Liesner R, Nolan B, Bátorová A, Haya S, Young G; Future of Immunotolerance Treatment Group. The changing face of immune tolerance induction in haemophilia A with the advent of emicizumab. Haemophilia 2019;25(4):676-684.

Pipe SW. Delivering on the promise of gene therapy for haemophilia. Haemophilia 2020 Jun 3. doi: 10.1111/hae.14027. Epub ahead of print. Pasi KJ, Rangarajan S, Mitchell N, Lester W, Symington E, Madan B, Laffan M, Russell CB, Li M, Pierce GF, Wong WY. Multiyear Follow-up of AAV5-hFVIII-SQ Gene Therapy for Hemophilia A. N Engl J Med 2020;382(1):29-40.

Nathwani AC, Reiss UM, Tuddenham EG, Rosales C, Chowdary P, McIntosh J, Della Peruta M, Lheriteau E, Patel N, Raj D, Riddell A, Pie J, Rangarajan S, Bevan D, Recht M, Shen YM, Halka KG, Basner-Ts- chakarjan E, Mingozzi F, High KA, Allay J, Kay MA, Ng CY, Zhou J, Cancio M, Morton CL, Gray JT, Srivastava D, Nienhuis AW, Davidoff AM. Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N Engl J Med 2014;371(21):1994-2004.

George LA, Sullivan SK, Giermasz A, Rasko JEJ, Samelson-Jones BJ, Ducore J, Cuker A, Sullivan LM, Majumdar S, Teitel J, McGuinn CE, Ragni MV, Luk AY, Hui D, Wright JF, Chen Y, Liu Y, Wachtel K, Winters A, Tiefenbacher S, Arruda VR, van der Loo JCM, Zelenaia O, Takefman D, Carr ME, Couto LB, Anguela XM, High KA. Hemophilia B gene therapy with a high- specific-avtivity Factor IX variant. N Engl J Med 2017;377(23):2215-2227.

Von Drygalski A, Giermasz A, Castaman G, Key NS, Lattimore S, Leebeek FWG, Miesbach W, Recht M, Long A, Gut R, Sawyer EK, Pipe SW. Etranacogene deza- parvovec (AMT-061 phase 2b): normal/near normal FIX activity and bleed cessation in hemophilia B. Blood Adv 2019;3(21):3241- 3247.

Peyvandi F, Garagiola I. Clinical advances in gene therapy updates on clinical trials of gene therapy in haemophilia. Haemophilia 2019;25(5):738-746.

Pierce GF, Kaczmarek R, Noone D, O’Mahony B, Page D, Skinner MW. Gene therapy to cure haemophilia: Is robust scientific inquiry the missing factor? Haemophilia 2020 Sep 10. doi: 10.1111/ hae.14131. Epub ahead of print. http://fdaaa.trialstracker.net/trial/ NCT03370913/

Stonebraker JS, Bolton-Maggs PHB, Brooker M, Evatt B, Iorio A, Makris M, O’Mahony B, Skinner MW, Coffin D, Pierce GF, Tootoonchian E. The World Federation of Hemophilia Annual Global Survey 1999- 2018. Haemophilia 2020;26(4):591-600.

Publicado
2021-03-22
Cómo citar
Ruiz-Sáez, A. (2021). Tratamiento moderno de la hemofilia y el desarrollo de terapias innovadoras.: Modern treatment of hemophilia and development of innovatives therapies. Investigación Clínica, 62(1), 73-95. https://doi.org/10.22209/IC.v62n1a07